Methods and Compositions for Administering an Active Agent to the Pleura of a Patient

ABSTRACT

A method for administering an active agent to a pleura of a patient includes preparing a composition including a foamable liquid and the active agent, incorporating a gas into the foamable liquid to create a foam containing the active agent, introducing the foam into a pleural cavity of the patient defined by the pleura, and contacting the pleura with the foam. A method of pleurodesis includes introducing a composition into a pleural cavity defined by pleurae of a patient, the composition including a foamable liquid and an active agent capable of causing inflammation and/or adhesion of the pleurae. A composition for treating a pleura of a patient includes a liquid component including a biocompatible composition having a viscosity which increases in response to an increase in temperature, and an active agent capable of causing inflammation and/or adhesion of the pleura.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/973,703, filed Apr. 1, 2014, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention, according to some embodiments, relates to methodsand compositions for administering one or more active agents to apatient. More particularly, the present invention in some embodimentsrelates to methods and compositions for administering one or more activeagents to the pleura of a patient. In some embodiments, the presentinvention relates to methods and compositions that are useful forpleurodesis. In some embodiments, the present invention relates tomethods and compositions that are useful for treating pleural effusions,particularly malignant pleural effusions.

BACKGROUND OF THE INVENTION

The pleura is a membrane which surrounds the lungs and has a two-layerstructure including an outer or parietal pleura that is normallyattached to the chest wall and an inner or visceral pleura that coversthe lungs and adjoining structures. The space between the inner andouter pleurae is referred to as the pleural cavity, pleural space, orintrapleural space.

For ease of illustration, reference is made to the appended FIGURE whichis a simplified diagram showing pleural cavity 1, visceral pleura 2, andparietal pleura 3 in relation to lungs 4 and intercostal muscle 5 of anexample human (adapted from OpenStax College. “Anatomy & Physiology.”Connexions. Jun. 19, 2013.).

In healthy patients a small amount of pleural fluid, typically a fewmilliliters, is usually present in the pleural cavity. This fluid isnormally produced and reabsorbed continuously such that no considerableaccumulation of fluid occurs in the pleural cavity. Certain pathologicalconditions can lead to an increase in pleural fluid production and/or adecrease in fluid absorption, resulting in a significant accumulation ofexcess fluid in the pleural cavity. Blood, pus, and/or other bodilyfluids may also accumulate in the pleural cavity under certainconditions. This pathologic collection of fluid in the pleural cavity isknown as a pleural effusion.

Pleural effusions may be caused by a number of medical conditionsincluding, for example, congestive heart failure, infections, pneumonia,pulmonary embolism, and cancers. Malignant pleural effusions refer to atype of pleural effusion in which the excess accumulation of fluid inthe pleural cavity is specifically caused by cancer. Malignant pleuraleffusions may be caused, for example, by lung cancer, breast cancer,lymphoma, and pleural mesothelioma.

Pleural effusions, including malignant pleural effusions, can impairnormal breathing by significantly limiting the expansion of the lungs.In some cases the excess fluid accumulation in the pleural cavitycompresses the lungs resulting in breathlessness and/or lung collapse.For some patients, treating the underlying cause of the pleuraleffusions (e.g., treating the cancer causing a malignant pleuraleffusion) may be sufficient to mitigate the pleural effusion. Othertreatments for pleural effusions include aspiration of the excess fluidor insertion of a chest tube (e.g., thoracic cather, tube thoracostomy,or intercostal drain) into the pleural cavity of the patient to drainthe excess fluid. While aspiration or drainage may provide immediaterelief for the patient, fluid accumulation and symptoms may reappearsuch that repeated aspirations or continuous drainage is required.

Pleurodesis, a procedure in which the pleural cavity is treated in anattempt to reduce or eliminate the potential pleural space, may be usedto treat patients suffering from recurrent pleural effusions by reducingor obliterating the potential space in which fluid may accumulate.Pleurodesis typically involves fusing together the outer and innerpleurae and may be carried out using surgical and/or chemical means.Examples of typical procedures for pleurodesis are described in Vaz etal., “Pleurodesis: technique and indications,” J Bras Pneumol. 2006;32(4):347-56, which is incorporated herein by reference in its entirety.Fusion of the inner and outer pleurae may be accomplished, for example,by triggering fibrosis or the formation scar tissue between the innerand outer pleurae to cause the pleural layers to fuse together. Surgicalpleurodesis may include, for example, mechanically irritating the pleuraand causing the layers of the pleura to scar together. This procedurecan be performed, for instance, by scraping the outer pleura with arough pad (e.g., via thoracotomy). In chemical pleurodesis, a chemicalagent which causes inflammation for inducing fibrosis between the innerand outer pleura, for example, may be introduced into the pleural cavity(e.g., via a catheter or chest drain) to fuse the inner and outerpleurae together. Certain chemical agents and procedures that may besuitable for pleurodesis are described in U.S. Pat. No. 6,103,695, whichis incorporated herein by reference in its entirety.

Chemical pleurodesis is sometimes preferred over surgical pleurodesissince chemical pleurodesis may be less invasive. However, treatmentsuccess can be suboptimal as substantial or adequate reduction of thepleural cavity can be difficult to achieve in some circumstances whenthe chemical agent is not effectively distributed throughout the pleuralcavity of the patient. When portions of the pleura are not sufficientlyexposed to the chemical agent, incomplete fusion of the pleural layersmay occur. For example, because the chemical agent used in chemicalpleurodesis is typically introduced in a liquid or slurry, the chemicalagent may collect at certain locations in the pleural cavity due togravity, possibly resulting in an uneven distribution of the chemicalagent. In some cases the chemical agent may not maintain contact withportions of the pleura for a sufficient amount of time to triggerfibrosis because, for example, the liquid or slurry drains to lowerregions of the pleural cavity.

SUMMARY OF THE INVENTION

The present invention, according to some embodiments, relates to methodsand compositions for administering one or more active agents to apatient. More particularly, the present invention in some embodimentsrelates to methods and compositions for administering one or more activeagents to the pleura of a patient. In some embodiments, the presentinvention relates to methods and compositions that are useful forpleurodesis. In some embodiments, the present invention relates tomethods and compositions that are useful for treating pleural effusions,for example, malignant pleural effusions. In further embodiments,methods and compositions of the present invention may be useful fortreating infections or bleeding in the pleural cavity, pneumothorax,and/or hemothorax.

Methods according to certain embodiments of the present inventionsinclude administering a composition comprising or consisting of afoamable liquid to a pleura of a patient. In some embodiments, a methodfor administering an active agent to a pleura of a patient includespreparing a composition comprising a foamable liquid and the activeagent, incorporating a gas into the foamable liquid to create a foamcontaining the active agent, and introducing the foam into a pleuralcavity of the patient defined by the pleura; and contacting the pleurawith the foam. As used herein, the term foamable liquid refers to aliquid having the ability to form a foam. In certain embodiments, thefoamable liquid by itself is an active agent.

In further embodiments, a method according to the present inventionincludes introducing a composition into a pleural cavity defined bypleurae of a patient, the composition comprising a foamable liquid andan active agent capable of causing inflammation and/or adhesion of thepleurae, contacting the pleurae with the composition for an amount oftime sufficient to initiate inflammation and/or adhesion of the pleuraeby the active agent, and allowing the pleurae to seal together to reducea volume of the pleural cavity. According to some of these embodiments,the foamable liquid is mixed with a gas to form a foam prior tointroducing the composition into the pleural cavity such that contactingthe pleurae with the composition includes contacting the pleurae withthe foam. In other embodiments, the foamable liquid is mixed with gasduring or after the composition is introduced into the pleural cavity.

In some embodiments, the foam has a volume of about 10 to about 1000times greater than the volume of the foamable liquid. In someembodiments, the foam comprises bubbles of the gas having a size rangeof about 1 mm to about 10 mm in diameter. In some embodiments, the gasmay include air, carbon dioxide, oxygen, hydrogen, helium, argon orcombinations thereof.

Some methods of the present invention further include removing at leasta portion of the foam from the pleural cavity after contacting thepleurae with the foam. In some embodiments, at least a portion of thegas is allowed to separate from the foam after contacting the pleuraewith the foam. For example, the foam may be allowed to collapse ordissipate within the pleural cavity of the patient. After the foam hascollapsed or dissipated, at least a portion of the residual liquid orgas may be absorbed by the patient's body or drained from the pleuralcavity according to some embodiments. In further embodiments, removingat least a portion of the foam from the pleural cavity includes one ormore of aspirating, draining, and intubation of the pleural cavity. Inother embodiments, at least a portion of the foam may be removed fromthe pleural cavity by allowing the foam to be absorbed by the patient'sbody.

In some embodiments, the foamable liquid may include, for example,liquid solutions, slurries, suspensions, or colloidal solutions. In someembodiments, the foamable liquid includes a gel or a compositionconfigured to form a gel (e.g., a hydrogel). In other embodiments, thefoamable liquid does not include a gel (e.g., a hydrogel) or across-linked polymer network. In some embodiments, the foamable liquidis an aqueous solution. In some embodiments, the foamable liquid mayfurther include one or more surfactants and/or proteins that areselected to modify the stability of the foam formed when the foamableliquid is admixed with a gas. In some embodiments, for example, thefoamable liquid includes albumin (e.g., human serum albumin), which maybe present in the foamable liquid at a concentration of about 5% toabout 25% by weight of the foamable liquid.

The active agent used in embodiments of the present invention may bedissolved, dispersed, suspended, or carried by the foamable liquid. Insome embodiments, the active agent is dissolved, dispersed, suspended,or carried by the foamable liquid prior to foaming the foamable liquid.The active agent may be present in an amount of about 0.1% to about 50%by weight of the foamable liquid according to some embodiments. In someembodiments, the foamable liquid itself is an active agent, for example,suitable for use in chemical pleurodesis.

In some embodiments, the active agent is a chemical agent useful forchemical pleurodesis. In some embodiments, the active agent includes asclerosing agent. In some embodiments, the active agent is selected tocause irritation, inflammation, fibrosis, and/or scarring of thepatient's pleura when introduced into the pleural cavity of the patient.In some embodiments, the active agent includes one or more agentsselected from the following: doxycycline, bleomycin, tetracycline,povidone iodine, talc, silica (e.g., fumed silica), and quinacrine. Insome embodiments, the active agents include a chemotherapy agent, anantibiotic, or combinations thereof. In some embodiments, the activeagent is an adhesive, for example, an adhesive adpated to adhere thepleural layers together. In some embodiments, the adhesive comprises oneor more agents selected from the group consisting of: collagen-basedadhesives, fibrin-based adhesives, cyanoacrylates, fibrin sealants,gelatin-resorcin-aldehydes, protein-aldehyde systems,polysaccharide-based adhesives, mussel adhesive proteins, and biomimeticglues.

In further embodiments, the present invention includes a composition foradministering an active agent to a pleura of a patient, the compositionincluding a liquid component comprising a biocompatible compositionhaving a viscosity which increases in response to an increase intemperature, and an active agent dissolved, dispersed, or suspended inthe liquid component, the active agent being capable of causinginflammation and/or adhesion of the pleurae. In some of theseembodiments, the viscosity of the biocompatible composition isconfigured to increase at least three times when the temperature of thebiocompatible composition increases from about 25° C. to about 37° C. Insome of these embodiments, the viscosity of the biocompatiblecomposition is configured to increase at least ten times when thetemperature of the biocompatible composition increases from about 25° C.to about 37° C. In some of these embodiments, the viscosity of thebiocompatible composition is configured to increase at least a hundredtimes when the temperature of the biocompatible composition increasesfrom about 25° C. to about 37° C. In some embodiments, the biocompatiblecomposition is selected to have a viscosity at about room temperaturethat is less than 500,000 cP, less than 400,000 cP, less than 300,000cP, less than 200,000 cP, less than 100,000, less than 50,000 cP, lessthan 10,000 cP, less than 5,000 cP, less than 1,000 cP, less than 500cP, less than 100 cP, less than 50 cP, less than 10 cP, less than 5 cP,or less than 1 cP. In some embodiments, the biocompatible composition isselected to have a viscosity at about human body temperature that is atleast 10,000 cP, at least 50,000 cP, at least 100,000 cP, at least200,000 cP, at least 300,000, at least 400,000 cP, at least 500,000 cP,at least 600,000 cP, at least 700,000 cP, at least 800,000 cP, at least900,000 cP, or at least 1,000,000 cP. In some embodiments, thebiocompatible composition is configured to form a gel afteradministration to the patient. In some embodiments, the biocompatiblecomposition includes one or more copolymers of ethylene oxide andpropylene oxide. In further embodiments, the biocompatible compositionincludes one or more poloxamers, xanthan gum, and water. The liquidcomponent may be a foamable liquid, according to some embodiments. Insome embodiments, the composition further includes a gas having a volumegreater than a volume of the liquid component. In other embodiments, theliquid component is not foamed before, during, and/or afteradministration to the patient. The active agent may be selected from thegroup consisting of selected from the group consisting of: doxycycline,bleomycin, tetracycline, povidone iodine, talc, silica, and quinacrineaccording to some embodiments. In other embodiments, the active agentmay be an adhesive, for example, selected from the group consisting ofcollagen-based adhesives, fibrin-based adhesives, cyanoacrylates, fibrinsealants, gelatin-resorcin-aldehydes, protein-aldehyde systems,polysaccharide-based adhesives, mussel adhesive proteins, and biomimeticglues.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is an illustration showing the parietal and visceral pleuraeof the lungs of a human.

DETAILED DESCRIPTION

The present subject matter will now be described more fully hereinafterin which representative embodiments are described. The present subjectmatter can, however, be embodied in different forms and should not beconstrued as limited to the embodiments set forth herein. Rather, theseembodiments are provided to describe and enable one of skill in the art.While particular embodiments described herein are illustrative ofmethods and compositions useful for pleurodesis, for example, in thetreatment of pleural effusions, the present invention is not intended tobe limited to these uses. Indeed, other treatments may benefit from theadvantages provided by the methods and compositions described herein.

The present invention, according to certain embodiments, generallyincludes methods and compositions for administering one or more activeagents to a patient. In some embodiments, the methods and compositionsof the present invention are particularly adapted for administering oneor more active agents to the pleura of a patient. In some embodiments,for example, the methods and compositions described herein are usefulfor treating pleural effusions (e.g., malignant pleural effusions). Inparticular, certain preferred embodiments of the invention relate tomethods and compositions that are useful for pleurodesis. Such methodsand compositions, for example, may be used to reduce or obliterate thepleural cavity of a patient to prevent fluid buildup in the pleuralcavity.

Some embodiments of the present invention relate to preparing acomposition including one or more active agents and introducing thecomposition into a pleural cavity of the patient. In some embodiments,the compositions of the present invention include flowable compositionscontaining one or more active agents. In some embodiments, thecompositions of the present invention are adapted to be introduced intothe pleural cavity of a patient, for example, via a catheter or a chestdrain. In some embodiments, the compositions may be sprayed, injected orpumped into the pleural cavity of the patient.

In some embodiments, the compositions of the present invention mayinclude homogeneous mixtures or heterogeneous mixtures. In someembodiments, the compositions may include one or more liquid componentswhich may be used to dissolve, suspend, disperse, or carry the one ormore active agents. In some embodiments, the one or more liquidcomponents are active agents. The liquid component may, for example,include liquid solutions, slurries, suspensions, or colloidal solutions.Moreover, the liquid component in some embodiments may include aqueousor non-aqueous liquids. In some embodiments, the liquid component isconfigured to undergo an increase in viscosity during and/or afterintroduction into the body of a patient (e.g., into the pleural cavity).In some embodiments, the liquid component forms a mucoadhesiveconfigured to adhere to the pleura of the patient. In some embodiments,the liquid component is or includes a gel, or a composition which isconfigured to form a gel (e.g., a hydrogel). In some embodiments, theliquid component is configured to form a gel after introduction into thebody of a patient (e.g., into the pleural cavity). In yet otherembodiments, the liquid component is not or does not form a gel (e.g., ahydrogel). In further embodiments, the compositions of the presentinvention may also include one or more components in a gaseous state. Insome embodiments, the compositions include a gas or mixture of gaseswhich may be admixed with the liquid component.

Compositions according to certain embodiments of the present inventioninclude a foamable liquid as the liquid component. As used herein, theterm foamable liquid refers to a liquid having the ability to form afoam. In some embodiments, the foamable liquid is configured to form afoam when the foamable liquid is admixed with a gas. As describedherein, the foamable liquid may include, for example, liquid solutions,slurries, suspensions, or colloidal solutions. In other embodiments, thefoamable liquid includes a gel or a composition which forms a gel (e.g.,a hydrogel). In other embodiments, the foamable liquid is not or doesnot form a gel (e.g., a hydrogel) or a cross-linked polymer network. Insome embodiments, the foamable liquid includes water. In someembodiments, the foamable liquid includes an aqueous solution,preferably an aqueous solution that can be absorbed by the patient'sbody without substantial adverse (e.g., toxic) effects. In someembodiments, the aqueous solution includes a saline solution. In someembodiments, the foamable liquid includes one or more of lipids,phospholipids, neutral lipids, and alcohols. In some embodiments, theliquid component is admixed with a gas to form a foam prior toadministration to the patient, as will be described further herein. Inother embodiments, the liquid component is configured to be administeredto a patient in an unfoamed state and foamed within the patient's body(e.g., within the pleural cavity). In yet other embodiments, the liquidcomponent is not foamed.

Gases useful in the foamed compositions of the present inventionpreferably include gases that can be readily instilled into the body ofthe patient without substantial adverse (e.g., toxic) effects. In someembodiments, the gas is selected from the group consisting of air,carbon dioxide, oxygen, hydrogen, helium, argon, and mixtures thereof.Preferably, according to some embodiments, the gas is not pure nitrogen.In other embodiments, the gas includes one or more organic compounds. Insome embodiments, the gas includes one or more hydrocarbons, forexample, n-butane, n-pentane, or other saturated low boiling pointaliphatic hydrocarbons. In further embodiments, the gas may include oneor more fluorocarbons and/or hydrofluorocarbons. Other aerosol spraypropellents known in the art which do not have substantial adverseeffects may also be used according to some embodiments. The gas in someembodiments includes vapors that may be, for example, produced from theevaporation or sublimation of a liquid or solid substance. In someembodiments, for example, the gas includes a volatile compound mixedwith the foamable liquid and which causes the foamable liquid to foam asthe volatile compound vaporizes. In some embodiments, the gas isgenerated from a chemical reaction, for example, an acid-base reaction.In some such embodiments, the foamable liquid may be or include achemical reactant that reacts to produce a gas.

In further embodiments, the liquid component includes one or moresurfactants. The one or more surfactants may include a biocompatiblefoaming agent selected to modify the stability of the foam formed whenthe foamable liquid is admixed with a gas. In some embodiments, thesurfactants may further function as a sclerosing agent. In someembodiments, one or more surfactants includes sodium tetradecyl sulfate.Other surfactants that may be useful according to certain embodiments ofthe present invention include phospholipids, neutral lipids, hydrophobicsurfactants, biocompatible soaps or detergents, and combinationsthereof.

In some embodiments, the liquid component includes one or morepolypeptides. In some embodiments, the liquid component includes one ormore proteins. In some embodiments, the one or more proteins include analbumin (e.g., human serum albumin). Other proteins that may be used inthe liquid component according to certain embodiments include surfactantassociated proteins, for example, surfactant associated proteins B or C.In some embodiments, the one or more proteins includes only albumin. Inother embodiments, the one or more proteins includes only surfactantassociated proteins. In some embodiments, the one or more proteinsincludes a combination of albumin and a surfactant associated protein.In some embodiments, the albumin and/or other proteins included in theliquid component enhances the liquid component's ability to form a foamwhen the liquid component is admixed with a gas. In some embodiments,the one or more proteins (e.g., albumin) is present in the liquidcomponent in an amount that is at least 0.5% by weight of the liquidcomponent. In some embodiments, the one or more proteins (e.g., albumin)is present in the liquid component in an amount that is at least 1% byweight of the liquid component. In some embodiments, the one or moreproteins (e.g., albumin) is present in the liquid component in an amountthat is at least 5% by weight of the liquid component. In someembodiments, the one or more proteins (e.g., albumin) is present in theliquid component in an amount that is at least 10% by weight of theliquid component. In some embodiments, the one or more proteins (e.g.,albumin) is present in the liquid component in an amount that is atleast 15% by weight of the liquid component. In some embodiments, theone or more proteins (e.g., albumin) is present in the liquid componentin an amount that is at least 20% by weight of the liquid component. Insome embodiments, the one or more proteins (e.g., albumin) is present inthe liquid component in an amount that is at least 25% by weight of theliquid component. In some embodiments, the one or more proteins (e.g.,albumin) is present in the liquid component in an amount that is atleast 30% by weight of the liquid component. In some embodiments, theone or more proteins (e.g., albumin) is present in the liquid componentin an amount from about 1% to about 10% by weight of the liquidcomponent. In some embodiments, the one or more proteins (e.g., albumin)is present in the liquid component in an amount from about 1% to about20% by weight of the liquid component. In some embodiments, the one ormore proteins (e.g., albumin) is present in the liquid component in anamount from about 1% to about 30% by weight of the liquid component. Insome embodiments, the one or more proteins (e.g., albumin) is present inthe liquid component in an amount from about 1% to about 40% by weightof the liquid component. In some embodiments, the one or more proteins(e.g., albumin) is present in the liquid component in an amount fromabout 1% to about 50% by weight of the liquid component. In someembodiments, the one or more proteins (e.g., albumin) is present in theliquid component in an amount from about 5% to about 25% by weight ofthe liquid component. In some embodiments, the one or more proteins(e.g., albumin) is present in the liquid component in an amount fromabout 10% to about 20% by weight of the liquid component. In someembodiments, the one or more proteins (e.g., albumin) is present in theliquid component in an amount no more than 50% by weight of the liquidcomponent.

In some embodiments, a liquid component includes or consists of abiocompatible composition having a viscosity which increases during orafter introduction into the body of the patient. In some embodiments, aliquid component includes or consists of a biocompatible compositionhaving a viscosity which increases in response to an increase intemperature (e.g., from about room temperature to about human bodytemperature). In some embodiments, the liquid component includes a gelor a composition which forms a gel. In some embodiments, where theliquid component includes a gel or a composition which forms a gel, theliquid component may or may not also include one or more proteins (e.g.,albumin or surfactant associated proteins), and may or may not includeone or more surfactants as described above. In preferred embodiments,the gel or composition which forms a gel exhibits mucoadhesiveproperties. In some embodiments, the gel or composition which forms agel exhibits mucoadhesive properties when or after being introduced intothe pleural cavity of a patient. In some embodiments, the gel orcomposition which forms a gel is configured to adhere to the inner andouter pleurae of the patient after introduction into the pleural cavity.In some embodiments, the gel or composition which forms a gel includesor consists only of a biocompatible, biodegradable hydrogel. In someembodiments, the gel or composition which forms a gel includes one ormore materials configured to form a gel during and/or after introductioninto the patient (e.g., into the pleural cavity). In some embodiments,the gel or composition which forms a gel is configured to increase inviscosity after introduction into the patient such that, for example,the gel or composition which forms a gel can be introduced into thepatient as a liquid and/or a foam. In some embodiments the gel orcomposition which forms a gel exhibits in situ reverse-thermal gelling.

In some embodiments, the liquid component includes or consists of a gel,or a composition which forms a gel, that is substantially liquid (lowviscosity) at about room temperature (e.g., about 20° C. to about 25°C.). In some embodiments, the viscosity of the gel or composition whichforms a gel is less than 800,000 centipoise (cP) at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 750,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 700,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 650,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 600,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 550,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 500,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 450,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 400,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 350,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 300,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 250,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 200,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 150,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 100,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 90,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 80,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 70,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 60,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 50,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 40,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 30,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 20,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 10,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 9,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 8,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 7,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 6,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 5,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 4,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 3,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 2,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 1,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 900 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 800 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 700 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 600 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 500 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 400 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 300 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 200 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 100 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 90 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 80 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 70 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 60 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 50 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 40 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 30 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 20 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 10 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 9 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 8 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 7 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 6 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 5 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 4 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 3 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 2 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 1 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.9 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.8 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.7 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.6 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.5 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.4 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.3 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.2 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is less than 0.1 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 0.1 cP to about 1 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 0.1 cP to about 1.5 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 0.1 cP to about 2 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 0.1 cP to about 5 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 0.1 cP to about 10 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 1 cP to about 10 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 1 cP to about 50 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 1 cP to about 100 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 100 cP to about 200 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 100 cP to about 500 cP atabout room temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 100 cP to about 1,000 cPat about room temperature. In some embodiments, the viscosity of the gelor composition which forms a gel is between about 1,000 cP to about2,000 cP at about room temperature. In some embodiments, the viscosityof the gel or composition which forms a gel is between about 1,000 cP toabout 5,000 cP at about room temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about1,000 cP to about 10,000 cP at about room temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 10,000 cP to about 20,000 cP at about room temperature.In some embodiments, the viscosity of the gel or composition which formsa gel is between about 10,000 cP to about 50,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 10,000 cP to about100,000 cP at about room temperature. In some embodiments, the viscosityof the gel or composition which forms a gel is between about 10,000 cPto about 500,000 cP at about room temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about100,000 cP to about 150,000 cP at about room temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 100,000 cP to about 200,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 100,000 cP to about250,000 cP at about room temperature. In some embodiments, the viscosityof the gel or composition which forms a gel is between about 100,000 cPto about 300,000 cP at about room temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about100,000 cP to about 350,000 cP at about room temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 100,000 cP to about 400,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 100,000 cP to about450,000 cP at about room temperature. In some embodiments, the viscosityof the gel or composition which forms a gel is between about 100,000 cPto about 500,000 cP at about room temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about200,000 cP to about 300,000 cP at about room temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 200,000 cP to about 400,000 cP at about roomtemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 200,000 cP to about500,000 cP at about room temperature. In some embodiments, the viscosityof the gel or composition which forms a gel is between about 300,000 cPto about 500,000 cP at about room temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about400,000 cP to about 500,000 cP at about room temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 400,000 cP to about 600,000 cP at about roomtemperature.

In some embodiments the liquid component includes or consists of a gel,or a composition which forms a gel, that is configured to undergogellation at temperatures above room temperature. In some embodimentsthe gel or composition which forms a gel is configured to have a gellingtemperature between 25° C. and 37° C. In some embodiments the gel orcomposition which forms a gel is configured to be in a solid or gelledstate at human body temperature (about 37° C.). In some embodiments, theviscosity of the gel or composition which forms a gel is at least 10,000cP at about human body temperature. In some embodiments, the viscosityof the gel or composition which forms a gel is at least 20,000 cP atabout human body temperature. In some embodiments, the viscosity of thegel or composition which forms a gel is at least 30,000 cP at abouthuman body temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 40,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 50,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 60,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 70,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 80,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 90,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 100,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 150,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 200,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 250,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 300,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 350,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 400,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 450,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 500,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 550,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 600,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 650,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 700,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 750,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 800,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 850,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 900,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 950,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is at least 1,000,000 cP at about humanbody temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 50,000 cP to about100,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about100,000 cP to about 200,000 cP at about human body temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 200,000 cP to about 300,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 300,000 cP to about400,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about400,000 cP to about 500,000 cP at about human body temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 500,000 cP to about 600,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 500,000 cP to about700,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about500,000 cP to about 800,000 cP at about human body temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 500,000 cP to about 900,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 500,000 cP to about1,000,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about600,000 cP to about 700,000 cP at about human body temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 600,000 cP to about 900,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 600,000 cP to about800,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about600,000 cP to about 900,000 cP at about human body temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 600,000 cP to about 1,000,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 700,000 cP to about800,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about700,000 cP to about 900,000 cP at about human body temperature. In someembodiments, the viscosity of the gel or composition which forms a gelis between about 700,000 cP to about 1,000,000 cP at about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is between about 800,000 cP to about900,000 cP at about human body temperature. In some embodiments, theviscosity of the gel or composition which forms a gel is between about800,000 cP to about 1,000,000 cP at about human body temperature. Insome embodiments, the viscosity of the gel or composition which forms agel is between about 900,000 cP to about 1,000,000 cP at about humanbody temperature.

In some embodiments, the viscosity of the gel or composition which formsa gel is configured to increase at least two to three times whentransitioning from about room temperature to about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is configured to increase at least two tofour times when transitioning from about room temperature to about humanbody temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is configured to increase at least threeto four times when transitioning from about room temperature to abouthuman body temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is configured to increase at least fivetimes when transitioning from about room temperature to about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is configured to increase at least tentimes when transitioning from about room temperature to about human bodytemperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is configured to increase at least ahundred times when transitioning from about room temperature to abouthuman body temperature. In some embodiments, the viscosity of the gel orcomposition which forms a gel is configured to increase at least athousand times when transitioning from about room temperature to abouthuman body temperature. In some embodiments, the increased viscosityand/or mucoadhesive properties can be advantageous by increasing thecontact time of the composition with the pleura. Moreover, by having alower viscosity when first introduced into the patient, the gel orcomposition which forms a gel can be more readily dispersed throughoutthe pleural cavity and better distributed over the surfaces of thepleura before the composition forms a gel.

The gel or composition which forms a gel according to some embodimentsof the invention includes one or more polymers. In some embodiments, thegel or composition which forms a gel includes one or more syntheticpolymers. In some embodiments, the gel or composition which forms a gelincludes one or more tri-block copolymers. In some embodiments, the gelor composition which forms a gel includes one or more copolymers ofethylene oxide and propylene oxide. In some embodiments, the gel orcomposition which forms a gel includes one or more poloxamers (e.g., oneor more poloxamers available under the trade names SYNPERONIC™ orPLURONICS®). In some embodiments, the gel or composition which forms agel includes one or more polysaccharides. In some embodiments, the gelor composition which forms a gel includes xanthan gum. In someembodiments, the gel or composition which forms a gel includes acombination of one or more copolymers of ethylene oxide and propyleneoxide and one or more polysaccharides. In some embodiments, the gel orcomposition which forms a gel includes a combination of one or morepoloxamers and xanthan gum. In some embodiments, the gel or compositionwhich forms a gel includes or consists of a combination of one or morepoloxamers, xanthan gum, and water. In some embodiments, the gel orcomposition which forms a gel includes biocompatible monomers which areconfigured to polymerize after introduction into the body of the patient(e.g., into the pleural cavity) to form a biocompatible gel.

In some embodiments, the gel or composition which forms a gel includesor consists of, for example, one or more of the compositions describedin U.S. Pat. Nos. 8,501,230, 8,691,278, and International ApplicationPublication No. WO 2009/073658, all of which are incorporated herein byreference in their entireties. In some embodiments, the gel orcomposition which forms a gel includes or consists of, for example,TRI-726 from TRILOGIC PHARMA described in Mondal, P. et al., “Evaluationof TRI-726 as a drug delivery matrix,” Drug Development and IndustrialPharmacy, 2011, pp 1-7, which is incorporated herein by reference in itsentirety. In some embodiments, the gel or composition which forms a gelincludes or consists of, for example, 10 to 25 parts by weight of one ormore poloxamers, 1 to 3 parts by weight of xanthan gum, and 72 to 89parts by weight of water. In some embodiments, the one or morepoloxamers includes one or more poloxamers selected from the groupconsisting of Poloxamer 407 (F127), Poloxamer 338 (F108), and Poloxamer188 (F68) available from BASF. In some embodiments, the one or morepoloxamers includes or consists only of Poloxamer 407 (F127). In someembodiments, the one or more poloxamers includes or consists only ofPoloxamer 338 (F108). In some embodiments, the one or more poloxamersincludes or consists only of Poloxamer 188 (F68). In some embodiments,the one or more poloxamers includes or consists only of a mixture ofPoloxamer 407 (F127) and Poloxamer 338 (F108). In some embodiments, theone or more poloxamers includes or consists only of a mixture ofPoloxamer 407 (F127) and Poloxamer 188 (F68). In some embodiments, theone or more poloxamers includes or consists only of a mixture ofPoloxamer 338 (F108) and Poloxamer 188 (F68). In some embodiments, theone or more poloxamers includes or consists only of a mixture ofPoloxamer 407 (F127), Poloxamer 338 (F108) and Poloxamer 188 (F68).

When the liquid components are admixed with a gas to form a foam inaccordance with certain embodiments, the resulting foam will have asubstantially greater volume in comparison to the volume of the unfoamedliquid component. This increase in volume is dependent on the amount ofgas which is mixed with the liquid component for form the foam.Accordingly, in some embodiments, the amount of gas that is mixed withthe liquid component may be selected based on the desired volumeincrease. For example in some embodiments, when the liquid component isfoamed, the resulting composition is configured to have a volume that isabout 1 to about 1000 times greater than the volume of the unfoamedliquid component. In some embodiments, the resulting composition has avolume that is about 1 to about 2 times greater than the volume of theunfoamed liquid component. In some embodiments, the resultingcomposition has a volume that is about 2 to about 3 times greater thanthe volume of the unfoamed liquid component. In some embodiments, theresulting composition has a volume that is about 3 to about 4 timesgreater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is about 4 toabout 5 times greater than the volume of the unfoamed liquid component.In some embodiments, the resulting composition has a volume that isabout 5 to about 6 times greater than the volume of the unfoamed liquidcomponent. In some embodiments, the resulting composition has a volumethat is about 6 to about 7 times greater than the volume of the unfoamedliquid component. In some embodiments, the resulting composition has avolume that is about 7 to about 8 times greater than the volume of theunfoamed liquid component. In some embodiments, the resultingcomposition has a volume that is about 8 to about 9 times greater thanthe volume of the unfoamed liquid component. In some embodiments, theresulting composition has a volume that is about 9 to about 10 timesgreater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is about 10 toabout 20 times greater than the volume of the unfoamed liquid component.In some embodiments, the resulting composition has a volume that isabout 20 to about 30 times greater than the volume of the unfoamedliquid component. In some embodiments, the resulting composition has avolume that is about 30 to about 40 times greater than the volume of theunfoamed liquid component. In some embodiments, the resultingcomposition has a volume that is about 40 to about 50 times greater thanthe volume of the unfoamed liquid component. In some embodiments, theresulting composition has a volume that is about 50 to about 60 timesgreater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is about 60 toabout 70 times greater than the volume of the unfoamed liquid component.In some embodiments, the resulting composition has a volume that isabout 70 to about 80 times greater than the volume of the unfoamedliquid component. In some embodiments, the resulting composition has avolume that is about 80 to about 90 times greater than the volume of theunfoamed liquid component. In some embodiments, the resultingcomposition has a volume that is about 90 to about 100 times greaterthan the volume of the unfoamed liquid component. In some embodiments,the resulting composition has a volume that is about 100 to about 200times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is about 200 toabout 300 times greater than the volume of the unfoamed liquidcomponent. In some embodiments, the resulting composition has a volumethat is about 300 to about 400 times greater than the volume of theunfoamed liquid component. In some embodiments, the resultingcomposition has a volume that is about 400 to about 500 times greaterthan the volume of the unfoamed liquid component. In some embodiments,the resulting composition has a volume that is about 500 to about 600times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is about 600 toabout 700 times greater than the volume of the unfoamed liquidcomponent. In some embodiments, the resulting composition has a volumethat is about 700 to about 800 times greater than the volume of theunfoamed liquid component. In some embodiments, the resultingcomposition has a volume that is about 800 to about 900 times greaterthan the volume of the unfoamed liquid component. In some embodiments,the resulting composition has a volume that is about 900 to about 1000times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 2times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 5times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 10times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 20times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 50times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 100times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 200times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least 500times greater than the volume of the unfoamed liquid component. In someembodiments, the resulting composition has a volume that is at least1000 times greater than the volume of the unfoamed liquid component.

The liquid component may be admixed with the gas to form a foam usingany suitable technique known in the art. In some embodiments, the liquidcomponent is agitated (e.g., shaken, whipped, or stirred) in thepresence of the gas. In some embodiments, the gas is bubbled into theliquid component using a pump or pressurized gas source. In someembodiments, the gas and the liquid component are passed through anarrow orifice, for example, the orifice of a syringe. In someembodiments, the liquid component and the gas are contained at apressure greater than atmospheric pressure (e.g., in a pressurized can)and foams as the liquid component and gas are released into atmosphericpressure. In other embodiments, the liquid component and gas are admixedand introduced using an injector, ejector, eductor-jet pump, aspiratorpump, or other device using a Venturi effect. Examples of such devicesare described in U.S. Pat. Nos. 2,569,683, 5,054,688, and 6,042,089,which are each incorporated herein by reference in their entirety. Insome embodiments, a predetermined amount of gas is admixed with theliquid component. Preferably the gas and liquid component are mixeduntil at least the desired volume of foam is produced.

In some embodiments, the foam comprises bubbles of the gas having a sizerange of about 0.1 mm to about 20 mm in diameter. In some embodiments,the foam comprises bubbles of the gas having a size range of about 0.5mm to about 15 mm in diameter. In some embodiments, the foam comprisesbubbles of the gas having a size range of about 1 mm to about 10 mm indiameter. In some embodiments, the foam comprises bubbles of the gashaving an average diameter ranging from about 1 mm to about 20 mm. Insome embodiments, the foam comprises bubbles of the gas having anaverage diameter ranging from about 1 mm to about 15 mm. In someembodiments, the foam comprises bubbles of the gas having an averagediameter ranging from about 1 mm to about 10 mm.

In a foamed state, the compositions according to some embodiments of thepresent invention may provide particular advantages in treatingconditions affecting the pleura or pleural cavity, for example, whenused for pleurodesis. In comparison to typical chemical pleurodesisprocedures, for example, foaming may improve contact between the activeagent and the patient's pleura, reduce the total amount of active agentneeded for pleurodesis, and/or leave less residual active agent in thepatient's pleural cavity according to some embodiments. These and otheradvantages may result from the increase in volume caused by foaming theliquid component which, for example, allows greater distribution the oneor more active agents throughout the pleural cavity. Moreover, in someembodiments, foaming may improve adherence of the composition with thepleura thereby increasing contact between the pleura and the activeagent.

As described, the active agent(s) useful in the compositions of thepresent invention may be dissolved, dispersed, suspended, or carried bythe liquid component. In some embodiments, the active agent(s) aredissolved, dispersed, suspended, or carried by the liquid componentprior to foaming the liquid component. In other embodiments, the activeagent(s) are added to the liquid component after the liquid componenthas been foamed. In some embodiments, the liquid component by itself isan active agent (e.g., capable of inducing fusion of the pleura). Insome embodiments, active agents useful in embodiments of the presentinvention are particularly adapted for use in chemical pleurodesis. Insome embodiments, the one or more active agents may be selected from anyagent known in the art to be useful in chemical pleurodesis. In someembodiments, the one or more active agents includes a sclerosing agent.In some embodiments, the active agents are selected to cause irritation,inflammation, fibrosis, and/or scarring of the patient's pleura whenintroduced into the pleural cavity of the patient. For example, in someembodiments, the active agents include one or more agents selected fromthe following: doxycycline, bleomycin, tetracycline, povidone iodine,talc, silica (e.g., fumed silica), and quinacrine. In some embodiments,the active agents include a chemotherapy agent, an antibiotic, orcombinations thereof. Other active agents that may be suitable for usein compositions according to embodiments of the present invention aredescribed in U.S. Pat. No. 6,103,695, which is incorporated herein byreference in its entirety.

In some further embodiments, compositions according to the presentinvention include at least one active agent that is an adhesivesubstance configured to adhere the layers of the patient's pleuratogether. Preferably the adhesive substance is capable of permanentlyadhering the layers of the pleura together. In some embodiments, theadhesive substance includes a hemostatic sealant. In some embodiments,the adhesive substance includes a fibrin- or collagen-based tissueadhesive. In some embodiments, the adhesive substance includes one ormore of fibrin sealants, gelatin-resorcin-aldehydes (e.g.,gelatin-resorcin-formaldehyde/glutaraldehyde glues), protein-aldehydesystems, polysaccharide-based adhesives, mussel adhesive proteins, andbiomimetic glues. In some embodiments, the adhesive substance includesone or more cyanoacrylate adhesives. The adhesive substance may be theonly active agent or included in combination with other active agents,for example, an active agent configured to cause irritation,inflammation, fibrosis, and/or scarring of the patient's pleura asdescribed above.

Compositions according to some embodiments of the present invention arenot necessarily limited to use in pleurodesis. Other conditions thataffect the pleura or pleural cavity of a patient may also be treatedaccording to certain methods and compositions of the present invention.In some embodiments, for example, compositions of the present inventionmay be useful in administering one or more active agents for treatinginfections or bleeding in the pleural cavity, penumothorax, orhemothorax. According to some of these embodiments, the compositionsinclude one or more active agents selected from antibiotics, sealants,hemostatic agents, and lytic agents. In other embodiments, thecompositions include one or more agents capable of reducing fluidformation or fluid leakage into the pleural cavity. In some embodiments,the compositions include one or more agents capable of increasing fluidreabsorption. Other active agents that can be administered by methodsand compositions of the present invention include cancer-treatingagents, nucleotides, vaccines, biopharmaceuticals, and therapeuticproteins or polypeptides.

The one or more active agents are preferably present in the compositionin a therapeutically effective amount. When used for pleurodesis, forexample, the one or more active agents are preferably present in atherapeutically effective amount sufficient to cause fusion of thepatient's pleura. In some embodiments, the one or more active agents arepresent in the composition from trace amounts to about 0.1% by weight ofthe liquid component. In some embodiments, the one or more active agentsare present in the composition from 0.001% to about 0.1% by weight ofthe liquid component. In some embodiments, the one or more active agentsare present in the composition from 0.01% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.02% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.03% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.04% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.05% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.06% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.07% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.08% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from 0.09% to about 0.1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition in an amount that is at least 0.1% by weightof the liquid component. In some embodiments, the one or more activeagents are present in the composition in an amount that is at least 0.5%by weight of the liquid component. In some embodiments, the one or moreactive agents are present in the composition in an amount that is atleast 1% by weight of the liquid component. In some embodiments, the oneor more active agents are present in the composition in an amount thatis at least 2% by weight of the liquid component. In some embodiments,the one or more active agents are present in the composition in anamount that is at least 5% by weight of the liquid component. In someembodiments, the one or more active agents are present in thecomposition in an amount that is at least 10% by weight of the liquidcomponent. In some embodiments, the one or more active agents arepresent in the composition in an amount that is at least 15% by weightof the liquid component. In some embodiments, the one or more activeagents are present in the composition in an amount that is at least 20%by weight of the liquid component. In some embodiments, the one or moreactive agents are present in the composition in an amount from about0.1% to about 50% by weight of the liquid component. In someembodiments, the one or more active agents are present in thecomposition in an amount from about 0.1% to about 40% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition in an amount from about 0.1% to about 30% byweight of the liquid component. In some embodiments, the one or moreactive agents are present in the composition in an amount from about0.1% to about 25% by weight of the liquid component. In someembodiments, the one or more active agents are present in thecomposition in an amount from about 0.1% to about 20% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition in an amount from about 0.1% to about 15% byweight of the liquid component. In some embodiments, the one or moreactive agents are present in the composition in an amount from about0.1% to about 10% by weight of the liquid component. In someembodiments, the one or more active agents are present in thecomposition in an amount from about 0.1% to about 9% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition in an amount from about 0.1% to about 8% byweight of the liquid component. In some embodiments, the one or moreactive agents are present in the composition in an amount from about0.1% to about 7% by weight of the liquid component. In some embodiments,the one or more active agents are present in the composition in anamount from about 0.1% to about 6% by weight of the liquid component. Insome embodiments, the one or more active agents are present in thecomposition in an amount from about 0.1% to about 5% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from about 0.1% to about 4% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from about 0.1% to about 3% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from about 0.1% to about 2% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition from about 0.1% to about 1% by weight of theliquid component. In some embodiments, the one or more active agents arepresent in the composition at less than 1% by weight of the liquidcomponent. In other embodiments, the one or more active agents arepresent in the composition in an amount greater than 50% by weight ofthe liquid component, e.g., from 50% to 60% by weight of the liquidcomponent, from 60% to 70% by weight of the liquid component, from 70%to 80% by weight of the liquid component, from 80% to 90% by weight ofthe liquid component, or from 90% to 99% by weight of the liquidcomponent. In certain embodiments, the liquid component by itself is anactive agent, for example, capable to cause irritation, inflammation,fibrosis, and/or scarring of the patient's pleura as described withoutthe use of additional active agents. According to some of theseembodiments, the amount of active agent present in the composition wouldbe equal to the weight of the liquid component.

The compositions according to certain embodiments of the invention canbe introduced into the pleural cavity of the patient using any suitabletechnique known in the art for introducing a fluid into the pleuralcavity. In some embodiments, techniques used to introduce chemicalagents during typical chemical pleurodesis procedures can also be usedto introduce compositions of the present invention into the pleuralcavity. In some embodiments, for example, the composition can beintroduced into the pleural cavity via a catheter or chest drain that isinserted into the pleural cavity. In some embodiments, the compositionsmay be injected into the pleural cavity of the patient. In someembodiments, the pleural cavity is first drained or aspirated of anyeffusions or other fluids prior to introducing the composition. In someembodiments, the composition can be introduced during open surgerywherein the pleural cavity is directly accessible. In some of theseembodiments, for example, the composition may be sprayed, poured, orotherwise directly introduced into the pleural cavity. In otherembodiments, the composition can be introduced during laparoscopic,videoscopic, or robotic surgery via minimally invasive techniques.

In some embodiments, the compositions are introduced into the pleuralcavity as a foam after the liquid component has been admixed with a gas.In other embodiments, the composition is introduced into the pleuralcavity before the liquid component is admixed with a gas. According tothese embodiments, the liquid component may then foamed within thepleural cavity by mixing the liquid component with a gas. In yet otherembodiments, the liquid component is foamed as it is introduced into thepleural cavity. For example, in some embodiments, both the liquidcomponent and a gas may be combined together as the components areintroduced into the cavity. As described, for example, in someembodiments the liquid component and the gas are contained at a pressuregreater than atmospheric pressure (e.g., in a pressurized can) and foamsas the liquid component and gas are released into the lower pressure ofthe pleural cavity. In other embodiments, the liquid component and gasare admixed and introduced into the pleural cavity using an injector,ejector, eductor-jet pump, aspirator pump, or other device using aVenturi effect.

In some embodiments, the total volume of foam produced is between about1 mL to about 100 mL. In some embodiments, the total volume of foamproduced is between about 1 mL to about 10 mL. In some embodiments, thetotal volume of foam produced is between about 1 mL to about 2 mL,between about 2 mL to about 3 mL, between about 3 mL to about 4 mL,between about 4 mL to about 5 mL, between about 5 mL to about 6 mL,between about 6 mL to about 7 mL, between about 7 ml, to about 8 mL,between about 8 mL to about 9 mL, or between about 9 mL to about 10 mL.In some embodiments, the total volume of foam produced is between about10 mL to about 100 mL. In some embodiments, the total volume of foamproduced is between about 10 mL to about 20 mL, between about 20 mL toabout 30 mL, between about 30 mL to about 40 mL, between about 40 mL toabout 50 mL, between about 50 mL to about 60 mL, between about 60 mL toabout 70 mL, between about 70 mL to about 80 mL, between about 80 mL toabout 90 mL, or between about 90 mL to about 100 mL. In someembodiments, the total volume of foam produced is between about 50 mL toabout 100 mL. In some embodiments, the total volume of foam produced isbetween about 75 mL to about 100 mL. In some embodiments, the totalvolume of foam produced is between about 100 mL to about 200 mL, betweenabout 200 mL to about 300 mL, between about 300 mL to about 400 mL,between about 400 mL to about 500 mL, between about 500 mL to about 600mL, between about 600 mL to about 700 mL, between about 700 mL to about800 mL, between about 800 mL to about 900 mL, or between about 900 mL toabout 1000 mL. In some embodiments, the total volume of foam produced isat least 100 mL. In some embodiments, the total volume of foam producedis at least 200 mL. In some embodiments, the total volume of the foamproduced is at least 500 mL. In some embodiments, the total volume ofthe foam produced is at least 750 mL. In some embodiments, the totalvolume of the foam produced is at least 1000 mL. In some embodiments,the total volume of the foam produced is between about 500 mL to about1000 mL. In some embodiments, the total volume of the foam produced isbetween about 750 mL to about 1000 mL. In some embodiments, the totalvolume of the foam produced is between about 1000 mL to about 1500 mL.In some embodiments, the total volume of the foam produced is betweenabout 1500 mL to about 2000 mL.

In some embodiments, as described above, one or more active agents aredissolved, suspended, or dispersed in the liquid component prior to theliquid component being foamed. In other embodiments, the one or moreactive agents can be added to the foam after the liquid component hasbeen foamed. In other embodiments, the liquid component by itself is anactive agent (e.g., capable of inducing fusion of the pleura). In someembodiments, the total amount of the one or more active agents to beintroduced into the pleural cavity may range from about 100 mg to about20 g, depending on the type of active agent used. For example, when talcis used as the active agent, the total amount of talc included in thecomposition may range from about 1 g to about 15 g, 2 g to about 12 g,from about 2.5 g to about 10 g, from about 3 g to about 7 g, or fromabout 4 g to about 6 g, according to some embodiments. In otherembodiments, where the active agent is doxycycline, bleomycin,tetracycline, quinacrine or combinations thereof, the total amount ofactive agent included in the composition may range, for example, fromabout 50 mg to about 2000 mg, about 100 mg to about 1000 mg, about 200mg to about 800 mg, from about 300 mg to about 700 mg, or from about 400mg to about 600 mg.

In certain embodiments, after the composition is introduced into thepleural cavity, the foam is allowed to contact the layers of the pleura.In some embodiments, contacting the layers of the pleura with the foamexposes the pleura to the one or more active agents that are dissolved,suspended, dispersed, and/or carried by the foam. As described above andherein, in some embodiments the foam allows greater distribution of theone or more active agents throughout the pleural cavity. For example, insome embodiments the volume of foam introduced into the pleural cavitymay be sufficient to fill substantially the entire pleural cavity suchthat substantially all of the patient's pleura is exposed to the one ormore active agents. Accordingly, certain embodiments of the presentinvention may avoid the problem faced during typical chemicalpleurodesis procedures wherein the chemical agent collects at certainlocations in the pleural cavity resulting in an uneven distribution ofthe chemical agent and incomplete fusion of the pleural layers.Moreover, in some embodiments, the foam may improve adherence of thecomposition with the pleura thereby increasing contact between thepleura and the one or more active agents.

In some embodiments particularly relating to pleurodesis, the foam ispreferably allowed to contact the pleura for at least an amount of timesufficient for the active agent to initiate a reaction in or have anactive effect on the layers of the pleura. In some embodiments, whenused for pleurodesis for example, the foam is preferably allowed tocontact the pleura for at least an amount of time sufficient for theactive agent to initiate inflammation and/or adhesion of the pleurallayers. In some embodiments, the desired contact time is at least 1minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, atleast 15 minutes, at least 30 minutes, at least 45 minutes, or at least60 minutes. In some embodiments, the desired contact time ranges fromabout 1 hour to about 24 hours, from about 2 hours to about 20 hours,from about 4 hours to about 18 hours, from about 6 hours to about 16hours, from about 8 hours to about 14 hours, or from about 10 hours toabout 12 hours.

In some embodiments, the foam may be allowed to remain within andabsorbed by the patient's body. Absorption may occur over a period ofone to seven days according to some embodiments. For example, in someembodiments, the foam is formulated to dissipate over time and theremaining residual liquid absorbed by the pleural layers. In otherembodiments, the residual liquid or a portion thereof is drained fromthe patient after or while the foam dissipates. Dissipation of the foamrefers to the gas escaping from the foam. In some embodiments, the foamis configured to dissipate within 1 hour, within 2 hours, within 4hours, within 8 hours, within 12 hours, or within 24 hours. In someembodiments, the foam is configured to begin dissipation immediatelyafter formation and/or administration to the patient. In someembodiments, the foam is configured to begin dissipation in less than aminute after formation and/or administration to the patient. In someembodiments, the foam is configured to dissipate in less than 1 hour,e.g., between 0 minutes to 60 minutes.

In other embodiments, the compositions of the present invention areactively removed from the pleural cavity after the desired amount ofcontact time has occurred. For example, in some embodiments, the foamintroduced into the pleural cavity is removed from the pleural cavityafter 5 minutes, after 30 minutes, after 1 hour, after 12 hours, after24 hours, etc. In some embodiments, the foam is removed before 24 hours.It should be understood that removal of the composition from the pleuralcavity may leave residual amounts of the composition and active agent(s)in the pleural cavity. Therefore removal of the compositions refers toremoval of at least a portion of the compositions. In some embodiments,the composition may be actively removed from the patient's pleuralcavity using any techniques known in the art for removing fluid from thepleural cavity. In some embodiments, removal is carried out using one ormore of aspirating, draining, and intubation. In some embodiments, atleast a portion of the composition is passively drained from thepatient's pleural cavity by gravity. In other embodiments, at least aportion of the composition is pumped from the pleural cavity. In someembodiments, at least a portion of the foam is allowed to dissipateprior to removal from the pleural cavity. The gas released from thedissipated foam may be allowed to be absorbed by the patient's body orremoved, e.g., by draining or aspirating the pleural cavity.

In certain other embodiments of the invention, the liquid component isnot or may not need to be foamed in order to effectively deliver theactive agent to the pleura. According to some of these embodiments, theliquid component is selected to have good adherence to the pleurallayers sufficient to maintain exposure of the pleural layers to theactive agent(s) that are dissolved, dispersed, suspended, or carried bythe liquid component. Some such embodiments may be achieved where theliquid component includes or consists of a gel, or a composition whichforms a gel (e.g., hydrogel), as described above. In some suchembodiments, the gel or composition which forms a gel is not admixedwith gas to form a foam. Instead, according to some these embodiments,the gel or composition which forms a gel may be introduced into thepatient in a substantially liquid (low viscosity) state and allowed toform a gel within the patient without foaming. The gel or compositionwhich forms a gel may be introduced into the patient as a liquid via acatheter, spray, injection, or other suitable technique known in the artand allowed to form a gel inside the pleural cavity. As the gel isformed, the gel contacts and adheres to the pleural layers and exposesthe pleural layers to the active agent(s). The example gels orcompositions which form gels described above may be used in this manneraccording to some embodiments of the invention. For example, the liquidcomponent may include or consist of a combination of one or morepoloxamers, xanthan gum, water, and one or more active agents. In someembodiments, the gel is configured to release the active agent over time(e.g., over a period of 1 to 10 days). Preferably the one or more activeagents are mixed with the gel or composition which forms a gel prior tointroduction into the patient. In some embodiments, the gel or acomposition which forms a gel and the one or more active agents areintroduced into the patient simultaneously. In other embodiments, theone or more active agents are introduced into the patient after the gelor a composition which forms a gel is introduced into the patient. Insome embodiments, the gel is actively removed from the patient after apredetermined time. In other embodiments, the gel is configured tobiodegrade and be absorbed by the patient's body. In some embodiments,the gel is configured to remain in the patient from about 1 to about 10days. Preferably, when used for pleurodesis, the gel is configured toremain in the patient for at least a period of time sufficient for theactive agent(s) to cause fusion of the pleura.

In some embodiments relating to pleurodesis, fusion of the inner andouter pleurae is achieved as a result of one or more active agentstriggering fibrosis or the formation scar tissue between the inner andouter pleurae. In other embodiments, where the active agent is anadhesive substance, fusion of the pleural layers is achieved by adheringthe layers together with the adhesive substance. In some embodiments,fusion of the pleural layers may occur within one to several days aftertreatment with the compositions of present invention. In preferredembodiments, the pleural cavity is obliterated as a result of the fusionof the pleural layers. In some embodiments, the volume of the pleuralcavity is reduced to at least an extent sufficient to prevent orminimize any pleural effusions.

It should be understood that various changes, substitutions, andalterations can be made herein without departing from the spirit andscope of the invention as defined by the appended claims. It should alsobe apparent that individual elements identified herein as belonging to aparticular embodiment may be included in other embodiments of theinvention. Moreover, the scope of the present application is notintended to be limited to the particular embodiments of the process,machine, manufacture, and composition of matter, means, methods andsteps described in the specification. As one of ordinary skill in theart will readily appreciate from the disclosure herein, processes,machines, manufacture, composition of matter, means, methods, or steps,presently existing or later to be developed that perform substantiallythe same function or achieve substantially the same result as thecorresponding embodiments described herein may be utilized according tothe present invention.

Furthermore, it should be understood that some of the descriptions ofthe present invention have been simplified to focus on elements that arerelevant for a clear understanding of the invention while eliminating,for the purposes of clarity, other elements that those of ordinary skillin the art will appreciate may also comprise a portion of the invention.However, because such elements are well known in the art, and becausethey do not necessary facilitate a better understanding of theinvention, a description of such elements is not provided herein.

1. A composition for treating a pleura of a patient, the compositioncomprising: a liquid component comprising a biocompatible compositionhaving a viscosity which increases in response to an increase intemperature; and an active agent dissolved, dispersed, or suspended inthe liquid component, the active agent being capable of causinginflammation and/or adhesion of the pleura. 2.-71. (canceled)